DESCRIPTION (Applicant's Abstract): Although externalizing psychopathology such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder (CD) have been consistently associated with the development of substance abuse, and although genes appear to influence risk for substance use disorders and these related forms of psychopathology, relatively little is known about the mechanism of genetic influence or the processes by which genetic factors combine with non-genetic factors to affect the development and course of substance abuse and these related behavioral disorders. In order to address these issues, we propose to initiate a longitudinal study of 400 pairs of 11-year-old twins, their mothers and their fathers. Twins will be identified from birth records and selected so that 314 of the pairs will have at least one member with ADHD, early-onset CD, or both. An additional, 86 pairs without ADHD or CD will also be included. When these 314 affected pairs are combined with adolescent twin pairs from our other ongoing research projects, we will have more than 500 pairs of twins having at least one member with either ADHD or early-onset CD (yielding over 700 individuals with one of these diagnoses), and over 650 twin pairs where both members have neither disorder. Twins and the parents will be initially assessed in-person at age 11, followed subsequently with brief telephone interviews annually and with a follow-up in-person assessment every three years. The in-person assessment will include comprehensive measurement of: 1) psychiatric status, 2) psychophysiological markers of risk, 3) individual-level risk factors including personality and achievement, and 4) environmental risk factors including attachment to parents, attachment to schools, and peer group models. For the initial period of funding, analysis of the age 11 intake and age 14 follow-up data will focus on characterizing genetic and environmental contributions to early onset substance use. Towards this end we will: 1) investigate the relationship of ADHD and early-onset CD with known risk factors for adolescent substance use (e.g., family and peer relationships) and with adolescent substance use onset prior to age 15, 2) complete biometrical analysis of the risk factor and diagnostic data to estimate the degree to which genetic and environmental factors contribute to individual differences on these factors, and 3) investigate genotype-environment interactional and correlational models of the contribution of ADHD and disinhibitory psychopathology on early onset adolescent substance use. Our intent is to continue to follow this cohort through early adulthood so that the applicability of these models for adult substance abuse can be assessed.